Diabetes mellitus is a systemic disease characterized by disorders in the metabolism of insulin, carbohydrates, fats and proteins, and in the structure and function of blood vessels. The primary symptom of acute diabetes is hyperglycemia, often accompanied by glucosuria, the presence in urine of large amounts of glucose, and polyuria, the excretion of large volumes of urine. Additional symptoms arise in chronic or long standing diabetes. These symptoms include degeneration of the walls of blood vessels. Although many different organs are affected by these vascular changes, the eyes appear to be the most susceptible. As such, long-standing diabetes mellitus, even when treated with insulin, is a leading cause of blindness.
There are two recognized types of diabetes. Juvenile onset, or ketosis-prone, diabetes develops early in life with much more severe symptoms and has a near-certain prospect of later vascular involvement. Control of this type of diabetes is often difficult. The second type of diabetes is adult onset, or ketosis-resistant, diabetes which develops later in life, is milder and has a more gradual onset.
One of the most significant advancements in the history of medical science came in 1922 when Banting and Best demonstrated the therapeutic effects of insulin in diabetic humans. However, even today, a clear of the basic biochemical defects of the disease is not known, and diabetes is still a serious health problem. It is believed that two percent or more of the population of the United States is afflicted with some form of diabetes.
The introduction of orally effective hypoglycemic agents was an important development in the treatment of diabetes. Hypoglycemic agents are useful in the treatment of hyperglycemia by lowering blood glucose levels. Oral hypoglycemic agents are normally used in the treatment of adult onset diabetes.
A variety of biguanide and sulfonylurea derivatives have been used clinically as hypoglycemic agents. However, the biguanides tend to cause lactic acidosis and the sulfonylureas, though having good hypoglycemic activity, require great care during use because they frequently cause serious hypoglycemia.
In Chemical & Pharmaceutical Bulletin, 30, 3563 (1982), Chemical & Pharmaceutical Bulletin, 30, 3580 (1982) and Chemical & Pharmaceutical Bulletin, 32, 2267 (1984), reference is made to a variety of thiazolidinediones which have blood glucose and lipid lowering activities. Antidiabetic activity of ciglitazone was also reported in Diabetes, 32, 804 (1983). However, these compounds have proven difficult to use because of insufficient activities and/or serious toxicity problems.
The present invention relates to orally active hypoglycemic agents capable of lowering blood glucose levels in mammals. Accordingly, one object of the present invention is to provide compounds having excellent hypoglycemic activity. Another object of the present invention is to provide hypoglycemic compounds which exhibit minimal toxicity in the ethylmorphine N-demethylation toxicity test system, and which do not cause unfavorable side reactions such as lactic acidosis or serious hypoglycemia. It is believed that compounds capable of achieving the objects of the present invention may be useful for treating diabetes. Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims.